Orally disintegrating tablets (ODT's), also called melt-in-mouth, fast-melting, mouth-dissolving, rapid-melt, orodispersible or quickly dissolving tablets are solid dosage forms that rapidly disintegrate in the oral human cavity without taking water. They thus overcome for example swallowing problems (especially for geriatric and paediatric patients) and may improve patient compliance. When an ODT is placed in the mouth, saliva causes it to disintegrate rapidly (usually within 60 seconds, preferably within 30 seconds and more preferably within 10 seconds) and to disperse the dosage form so that the saliva contains the medicinal substance. The patient either swallows the saliva-substance mixture such that it reaches the stomach, or a larger part (if not all) of the medicinal substance is absorbed through the mouth, pharynx and/or esophagus before it reaches the stomach, thus preventing first pass metabolism of the medicinal substance, and therewith enhancing the bioavailability of it.
A variety of medicinal substances and/or combinations thereof can be used as the active ingredient in the ODT such as for example analgesics and anti-inflammatory agents, antacids, anthelmintics, anti-arrhythmic agents, anti-bacterial agents, anti-coagulants, anti-depressants, anti-diabetics, anti-diarrheals, anti-epileptics, anti-fungal agents, anti-gout agents, anti-histamines, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosurpressants, anti-psychotics, anti-protozoal agents, anti-rheumatics, anti-thyroid agents, anti-viral agents, anxiolytics, sedatives, hypnotics and neuroleptics, beta-blockers, cardiac inotropic agents, corticosteroids, cough suppressants, cytotoxics, decongestants, diuretics, enzymes, anti-parkinson agents, gastro-intestinal agents, histamine receptor antagonists, lipid regulating agents, local anaesthetics, neuromuscular agents, nitrates and anti-anginal agents, opioid analgesics, proteins, peptides, recombinant drugs, sex hormones, contraceptives, spermicides, stimulants etc.
A process for the preparation of ODT's (in this specification also denoted as “disintegrating tablets”) is known i.a. from U.S. Pat. No. 5,384,124 assigned to Farmalyoc. In the known process a paste comprising one or more medicinal substances is formed, which paste is mechanically divided into unitary doses having a well defined shape and volume, by distributing the paste in cavities of predetermined shape and size, which cavities are present in a polyvinyl chloride carrier element. After distributing the paste, the carrier element is put in a lyophiliser and the paste is freeze-dried. This way, each unitary dose is formed into a tablet. The advantage of the freeze-drying process is not only that the medicinal substance is brought in a very stable form, but also that a solid dosage form is obtained that disintegrates upon contact with a liquid. In particularly, if the paste originally was based on water as the carrying solvent (the term “solvent” includes any liquid medium may serve as a carrier for other substances), such a tablet will normally disintegrate upon contact with water or a water based fluid such as saliva.
The known method is being widely used in the life-sciences industry (see for example “Orally disintegrating tablets: an overview of melt-mouth tablet technologies and techniques” by Deepak Kaushik, Harish Dureja and T. R. Saini, Maharishi Dayanand University and Shri G.S. Institute of Technology and Science, as published in “Tablets and Capsules”, 30 Jul. 2004). In particular technologies such as Zydis (Catalent Pharma Solutions, Somerset, N.J., USA) and Lyoc (Laboratoires Farmalyoc, Maisons-Alfort, France) use this known process. Typically the starting paste or fluid formulation is prepared and dosed into a preformed blister pack. This pack, i.e. the material present in the pack, is then frozen and subjected to freeze-drying to remove water. The resultant structures are inherently very porous and rapidly disintegrate when they contact saliva. Indeed, this method is very advantageous in that tablets can be made that very rapidly disintegrate, show adequate pharmacokinetic characteristics, better patient compliance and higher bioavailability when compared with reference oral solid formulations, and side-effect reduction (see “Fast-Melting Tablets: Developments and Technologies” by Luca Dobetti, in Pharmaceutical Technology Drug Delivery, 2001, pp 44-50). Known disadvantages are that the tablets have a relatively poor mechanical stability and high cost of production. These disadvantages however are believed to be inherent due to the freeze-dry process used: Freeze-drying needs expensive equipment and inherently leads to mechanically less stable tablets when compared e.g. to traditional compression techniques. Due to this fact the known process takes place by using the final tablet package (i.e. the blister package) as a carrier throughout the complete process. This inherently means that each production step has to be adjusted such that it can be used in conjunction with this particular package. This limits the freedom of operation in the various manufacturing steps and thus increases cost price even further. However, given the advantages of freeze-dried products as disintegrating tablets, the inherent high cost price of the manufacturing process is accepted by the manufacturing practitioner.
It is noted that other methods to arrive at ODT's are known from the prior art. For example, WO 93/12770 and US 2006/0057207 (both assigned to Pfizer Inc.) describe a method wherein the tablets are actively shaped over substantially their entire surface by compressing the frozen pellets in a closed mould. This known method thus defers from passively obtaining a tablet shape, for example by using a passively arrived shape that occurs through the mere action of gravity and surface tension. This way a predetermined shape can be arrived at easily in a controlled manner. This method is disadvantageous however in that it requires a rather complex die-and-punch assembly that is prone to leakage of the fluid formulation from the cavity (i.e. the closed mould). Also, frozen pellets tend to stick to either the die or punch due to the use of compression forces. An advantage indeed is that by compressing the frozen pellet, good mechanical properties are obtained which allow the frozen pellet to be taken out of the cavity integrally.
From U.S. Pat. No. 5,382,437 and EP 0 450 141 yet another method is known wherein the fluid formulation is brought over into open cavities of a solid element which is at room temperature, whereafter this element is brought over in a freezer for 30-60 minutes. This appears to be advantageous since the fluid formulation namely will nicely fill the cavity, thus leading to a frozen pellet of a size and shape that exactly corresponds to the size and shape of the cavity, and thus leading to a predictable pellet form. Disadvantages however are that a cooling-heating cycle has to take place with this method and also that the entire process is relatively slow. Also, there is a risk of loosing fluid from the cavity upon filling them with the (low viscosity) fluid formulation.